Process for the preparation of 4,4-dimethyl-6-ethynylthiochroman

ABSTRACT

An improved process for the preparation of key intermediates for tazarotene, 4,4-dimethyl-6-ethynylthiochroman, is provided comprising (a) reacting 4,4-dimethyl-6-acetylthiochroman of the formula 
                         
with an acid chloride and an amido-group containing compound of the general formula
 
                         
wherein R is hydrogen or a hydrocarbyl of from 1 to 15 carbon atoms and R 1  and R 2  can be the same or different and are hydrocarbyls of from 1 to 15 carbon atoms or R 1  and R 2  together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic group, optionally containing one or more additional heterocyclic atoms, or one of R 1  and R 2  together with the nitrogen atom to which it bonded are joined together with the carbonyl radical to form a heterocyclic group, optionally containing one or more additional heterocyclic atoms to form a β-chloro vinyl carbonyl compound intermediate of the general formula
 
                         
wherein R has the aforestated meanings; and (b) reacting the β-chloro vinyl carbonyl compound intermediate with an alkali metal to provide the 4,4-dimethyl-6-ethynylthiochroman.

CLAIM FOR PRIORITY

This application is a continuation of U.S. patent application Ser. No.10/883,880, filed Jul. 2, 2004, now U.S. Pat. No. 6,963,002 which claimspriority to U.S. Provisional Application No. 60/580,494, filed Jun. 17,2004, and Indian Provisional Application No. 685/MUM/2003, filed Jul. 4,2003, the contents of each of which are incorporated herein by referencein their entireties.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention generally relates to an improved process for thepreparation of intermediates for tazarotene. More specifically, thepresent invention relates to an improved process for the preparation ofthe intermediate 4,4-dimethyl-6-ethynylthiochroman using a VilsmeierHaack reaction.

2. Description of the Related Art

The present invention is directed towards an improved process for thepreparation of intermediates of tazarotene (also known asethyl-6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]) of Formula I:

Tazarotene is a member of the acetylenic class of retinoids and is aprodrug that is converted to its active drug form, known as AGN 190299,in most biological systems by rapid deesterificaion of the cognatecarboxylic acid of tazarotene. AGN 190299 binds to all three members ofthe retinoic acid receptor (RAR) family: RARα, RARβ, RARγ. AGN 190299shows relative selectivity for the RARβ and RARγ and may modify geneexpression. Tazarotene is used in the treatment of psoriasis and iscommercially available under the trade name Tazorac®.

A key intermediate in the preparation of tazarotene,4,4-dimethyl-6-ethynylthiochroman (II), is prepared as shown in SchemeI:

Thiophenol (1) and 1-bromo-3-methyl-2-butene (2) are heated at refluxwith sodium hydroxide in acetone resulting inphenyl-3-methylbut-2-enylsulfide (3). The phenyl-3-methylbut-2-enylsulfide (3) is cyclized by refluxing with phosphorus pentoxide andphosphoric acid in benzene to yield 4,4-dimethylthiochroman (4). The4,4-dimethylthiochroman (4) is reacted with acetyl chloride catalyzed bytin (IV) chloride (SnCl₄) in benzene resulting in4,4-dimethyl-6-acetylthiochroman (5). The4,4-dimethyl-6-acetylthiochroman (5) is dehydrated with lithiumdiisopropylamide (LDA) and diethyl chlorophosphate in tetrahydrofuran(THF) results in the initial 6-ethenyl phosphonate intermediate (6).This intermediate undergoes further reaction with two equivalents of LDAto give 4,4-dimethyl-6-ethynylthiochroman (II).

The main disadvantages of this process include the use of difficultreagents, such as LDA, which is moisture sensitive, expensive,pyrophoric, and difficult to handle on a commercial scale, and diethylchlorophosphate, which is highly toxic and corrosive. The process isalso time consuming and includes low temperatures in an inertatmosphere, which is difficult to achieve on a commercial scale.

Accordingly, there remains a need for an improved process for preparing4,4-dimethyl-6-ethynylthiochroman that eliminates and reduces thedrawbacks of the prior art in a convenient and cost efficient manner ona commercial scale.

SUMMARY OF THE INVENTION

One aspect of the present invention is the preparation of a keyintermediate of tazarotene, 4,4-dimethyl-6-ethynylthiochroman, via aVilsmeier Haack reaction. The Vilsmeier Haack reaction comprises (a)reacting 4,4-dimethyl-6-acetylthiochroman of the formula

with an acid chloride and an amido-group containing compound of thegeneral formula

wherein R is hydrogen or a hydrocarbyl of from 1 to about 15 carbonatoms and R¹ and R² can be the same or different and are hydrocarbyls offrom 1 to about 15 carbon atoms or R¹ and R² together with the nitrogenatom to which they are bonded are joined together to form a heterocyclicgroup, optionally containing one or more additional heterocyclic atoms,or one of R¹ and R² together with the nitrogen atom to which it isbonded are joined together with the carbonyl radical to form aheterocyclic group, optionally containing one or more additionalheterocyclic atoms to form a β-chloro vinyl carbonyl compoundintermediate of the general formula

wherein R has the aforestated meanings; and (b) reacting the β-chlorovinyl carbonyl compound intermediate with an alkali metal to provide the4,4-dimethyl-6-ethynylthiochroman.

The advantages of the present invention include:

1) The process may be performed without the isolation and purificationof intermediates after each step. The intermediates of the presentinvention are advantageously formed in a solvent which can be used infurther steps of the synthesis.

2) Avoids the use of low temperatures (e.g., −78° C.) which is expensiveto work in on a commercial scale.

3) Avoids the use of difficult reagents such as LDA, benzene, diethylchlorophosphate and diethyl ether. Each of these reagents presentsvarious hazards which make them particularly difficult to handle whenworking in commercial quantities.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In one aspect of the process of the present invention,4,4-dimethyl-6-ethynylthiochroman can be prepared by a process includingat least a Vilsmeier Haack reaction that forms a β-chloro vinyl carbonylcompound intermediate and then reacting the intermediate with an alkalimetal to form the 4,4-dimethyl-6-ethynylthiochroman. In a first step ofthe process of the present invention, 4,4-dimethyl-6-acetylthiochromanof the formula

is reacted with an acid chloride and an amido-group containing compoundof the general formula

wherein R is hydrogen or a hydrocarbyl of from 1 to about 15 carbonatoms, preferably from 1 to about 12 carbon atoms and more preferablyfrom 1 to 6 carbon atoms including, by way of illustration,unsubstituted straight or branched aliphatic, cycloaliphatic andaromatic groups and cycloaliphatic and aromatic groups substituted withone or more straight or branched aliphatic, cycloaliphatic and/oraromatic groups. Thus, for example, R may be hydrogen, an alkyl group of1 to about 6 carbon atoms or a phenyl group. As one skilled in the artwill readily appreciate, when R is hydrogen the resulting β-chloro vinylcarbonyl compound intermediate formed in this step will be a β-chlorovinylaldehyde intermediate and when R is a hydrocarbyl the resultingβ-chloro vinyl carbonyl compound intermediate formed in this step willbe a β-chloro vinylketone intermediate. R¹ and R² can be the same ordifferent and are hydrocarbyls of from 1 to about 15 carbon atoms,preferably from 1 to about 12 carbon atoms and more preferably from 1 to6 carbon atoms including, by way of illustration, unsubstituted straightor branched aliphatic, cycloaliphatic and aromatic groups andcycloaliphatic and aromatic groups substituted with one or more straightor branched aliphatic, cycloaliphatic and/or aromatic groups.Alternatively, R¹ and R² together with the nitrogen atom to which theyare bonded are joined together to form a heterocyclic group, optionallycontaining one or more additional heterocyclic atoms (e.g., O, S, N,etc.), for example, cyclic amines such as pyrrolidine, piperidine,piperazine, morpholine and the like. Alternatively, one of R¹ and R²together with the nitrogen atom to which it is bonded are joinedtogether with the carbonyl radical to form a heterocyclic group,optionally containing one or more additional heterocyclic atoms, such asa pyrrolidone and the like. This reaction advantageously forms aVilsmeier Haack reagent, β-chloro vinyl carbonyl compound intermediateof the general formula

wherein R has the aforestated meanings.

Examples of the foregoing amido-group containing compounds include, butare not limited to, dimethyl formamide, N-methyl formanilide, N-formylpiperidine, N-formyl morpholine, dimethyl acetamide, N-methylpyrrolidone, N,N-dimethyl benzamide and the like and mixtures thereofwith dimethyl formamide being preferred. Generally, the amido-groupcontaining compounds will be present in an amount ranging from about 45to about 90 wt. percent and preferably from about 55 to about 75 wt.percent, based on the total weight of the reaction mixture.

The acid chlorides for use in the process of the present invention areused to convert formamide derivatives and react with the4,4-dimethyl-6-ethynylthiochroman to form the β-chloro vinyl carbonylcompound intermediates. Any acid chloride may be used herein including,for example, phosphorous oxychloride (POCl₃). In one embodiment of thepresent invention, the acid chloride is selected from the groupconsisting of phosphorous oxychloride, thionyl chloride, phosgene andoxalyl chloride. The acid chloride may be present in a ratio of about1:3 (w/v) to about 1:5 (w/v) with respect to4,4-dimethyl-6-acetylthiochroman. The acid chloride may be addeddropwise to the 4,4-dimethyl-6-acetylthiochroman in the amido-groupcontaining compound over a time period of from about 1 to about 2 hoursat a temperature ranging from about −10° C. to about 100° C. Afteraddition of the acid chloride, the reaction time for the Vilsmeier Haackreaction may be about 4 to about 8 hours, and the reaction temperaturemay range from about −10° C. to about 35° C. When the Vilsmeier Haackreaction of the present invention is carried out at a temperature belowabout 10° C., the impurity profile is advantageously reduced.

As one skilled in the art will readily appreciate, the foregoingreaction may be carried out in one of two ways: (1) by adding the4,4-dimethyl-6-acetylthiochroman to the amido-group containing compoundand then adding the acid chloride; or (2) by adding the acid chloride tothe amido-group containing compound and then adding the4,4-dimethyl-6-acetylthiochroman.

Following the reaction of the 4,4-dimethyl-6-acetylthiochroman with theamido-group containing compound and acid chloride, it may be desirableto add a suitable solvent to the reaction mixture to extract the desiredβ-chloro vinyl carbonyl compound intermediate. Useful solvents include,but are not limited to, chlorinated alkane solvents such asdichloromethane, chloroform, carbon tetrachloride and the like andmixtures thereof. The solvent is generally added in an amount of fromabout 0 to about 30 wt. percent

Next, the Vilsmeier Haack reaction product can be reacted with an alkalimetal to form the 4,4-dimethyl-6-ethynylthiochroman. Useful alkalimetals include, but are not limited to, sodium hydroxide and potassiumhydroxide and the like and mixtures thereof. The reaction is ordinarilycarried out at a temperature ranging from about 20° C. to about 100° C.Useful alkali metal include, but are not limited to, sodium hydroxide,potassium hydroxide, lithium hydroxide and the like and mixturesthereof. The alkali metal is ordinarily added in a molar ratio of about1:4 to about 1:8 with respect to the β-chloro vinyl carbonyl compoundintermediate. It is particularly advantageous to carry out the reactionin step (b) in an ether type solvent medium. Useful ether type solventsinclude, but are not limited to, a dialkyl ether wherein the alkylgroups are the same or different and are from 1 to about 12 carbonatoms, e.g., dimethylether, diethylether and di-i-propylether; dioxane;tetrahydrofuran; pyran and mixtures thereof. The solvent will ordinarilybe present in an amount ranging from about 1:2 w/v to about 1:30 w/vwith respect to the reactants, i.e. for every 1 gram of a reactant, 2 to30 volume of the ether type solvent may be used. The reaction time willordinarily range from about 30 minutes to about 18 hours. The reactionmixture may then be quenched with saturated ammonium chloride.

In a preferred embodiment of the process of the present invention, thereaction includes reacting 4,4-dimethyl-6-acetylthiochroman (5) withdimethyl formamide and phosphorous oxychloride to form a Vilsmeier Haackreagent, β-chloro vinylaldehyde (7) and then adding sodium hydroxide toform 4,4-dimethyl-6-ethynylthiochroman (II) as shown in Scheme II:

Generally, to prepare the starting material4,4-dimethyl-6-acetylthiochroman, thiophenol may be reacted with astrong base in about equimolar amounts in ethylene dichloride (EDC) andmethanol at reflux. The mixture of methanol and ethylene dichloride (1:1v/v) may vary from about 1:12 w/v to about 1:15 w/v with respect to thethiophenol. The strong base is preferably an alkali metal hydroxide,such as, for example, sodium hydroxide. 1-Bromo-3-methyl-2-butene isadded in about equimolar amounts and the reaction mixture may berefluxed for about 8 to about 12 hours to form phenyl-3-methylbut-2-enylsulfide.

The phenyl-3-methylbut-2-enyl sulfide is present in the EDC layer anddoes not need to further purified or separated prior to reacting it withphosphorous pentoxide in the presence of phosphoric acid. The reactionis heated to reflux with stirring for about 8 to about 12 hours. Thisreaction closes the ring of the sulfide forming 4,4-dimethylthiochroman.

The 4,4-dimethylthiochroman is present in the EDC layer and also doesnot need to be further purified or separated prior to reacting it withacetyl chloride in the presence of aluminum chloride. The reactionmixture is stirred for about 30 minutes to about 3 hours at atemperature ranging from about −10° C. to about 10° C. The reaction isquenched and the product is 4,4-dimethyl-6-acetylthiochroman which ispresent in the EDC layer. The product may be used without furtherpurification to perform the Vilsmeier Haack reaction.

The following examples are provided to enable one skilled in the art topractice the invention and are merely illustrative of the invention. Theexamples should not be read as limiting the scope of the invention asdefined in the claims.

EXAMPLE 1 Preparation of3-[4,4-dimethylthiochroman-6-yl]-3-chloro-2-propene-1-al

In a 500 ml 4-necked round bottom flask fitted with a mechanical stirrerand a reflux condenser, 6-acetyl-4,4-dimethylthio-chroman (22 g) anddimethylformamide (38 ml) are added at a temperature in the range offrom about 35° C. to about 95° C. under stirring. The reaction mixtureis then cooled to a temperature in the range of from about −5° C. toabout 0° C. Phosphorus oxychloride (17.2 g) is added to the reactionmixture dropwise over about 30 minutes. Following the addition of thephosphorous oxychloride, the reaction mixture is maintained at atemperature in the range of from about 10° C. to about 15° C. for about8 hours to about 10 hours. After completion of the reaction asdetermined by TLC, the reaction mixture is added to cold water (100 ml)at a temperature of from about 0° C. to about 5° C. containing sodiumacetate (25 g). The aqueous layer is extracted with dichloromethane (200ml×3). The organic layer is washed with demineralized water (100 ml×3)until it becomes neutral.

The dichloromethane layer is concentrated on a rotavapor bath at atemperature in the range of from about 25° C. to about 30° C. underplant vacuum until no more drops are observed. The resulting residualoil is purified by flash chromatography with petroleum ether and ethylacetate (9:1 mixture) resulting in a pale yellow oil, weighing about 22g, yield of about 82%, purity of about 98% (HPLC). The IR (neat) showsthe following stretching 2900 cm⁻¹ (C—H str), 2750 cm⁻¹ (C—H str), 1690cm⁻¹ (—C═O str), 1620 cm⁻¹ (—C═C-str), 760 cm⁻¹ (—C═C—Cl str). The1H-NMR (CDCl₃) using TMS as internal standard shows the followingsignals at δ 1.35 (6H, s) 1.92-1.98 (2H, m), 3.02-3.08 (2H, m), 5.5 (1H,s), 7.13 (1H, d 8.6 Hz), 7.58 (1H, dd, J 8.6 Hz, 2H), 7.99 (1H, d, J 2Hz), 8.9 (s, 1H). The CI mass shows m/z 266 (M+).

Preparation of 4,4-dimethyl-6-ethynylthiochroman

In a 250 ml 4-necked round bottom flask fitted with a mechanical stirrerand reflux condenser, water (41.3 ml) and sodium hydroxide (5.22 g,0.1305M) are added and heated to a temperature in the range of fromabout 80° C. to about 90° C. The reaction mixture is stirred, and asolution of 3-[4,4-dimethylthiochroman-6-yl]-3-chloro-2-propene-1-al(3.0 gm, 0.0113 M) is added dropwise in 1,4-dioxane (52.2 ml) undervigorous stirring. The reaction mixture is maintained at a temperaturein the range of from about 80° C. to about 90° C. for about 2 hours.After completion of the reaction as determined by TLC, the solvents aredistilled off and the product is extracted with ether (15 ml×3). Theether layer is washed with brine (15 ml×3). The organic layer is driedover sodium sulfate, and the solvent is distilled off to get an oilyresidue. The resulting crude oil is distilled under high vacuum and thevapors are collected at a temperature of about 126° C./0.2 mm as themain product. The main fraction appears as red viscous oil, which uponstanding crystallized. Net wt of about 2.00 g, yield of about 87.68%;m.p. in the range of from about 69° C. to about 72° C., purity of about98% (HPLC). The IR (neat) shows the following absorptions: 3200 cm⁻¹(C—H-str), 2950 cm⁻¹ (—C═C—H str), 2100 cm⁻¹ (—C═C—). The 1H-NMR(CDCl₃), TMS as internal standard shows the following signals δ 1.35(6H, s), 1.92-1.98 (2H, m), 3.02-3.08 (3H, m), 7.13 (1H, d 8.6 Hz), 7.58(1H, dd, J 8.6 Hz, 2 Hz), 7.99 (1H, d, J 2 Hz). The CI/MS shows m/z 202(M+).

EXAMPLE 2 Preparation of phenyl-3-methylbut-2-enyl sulfide

In a 5 L 4-neck round bottom flask, methanol (1400 ml) and thiophenol(200 g) were added under stirring at a temperature ranging from about25° C. to about 35° C. Sodium hydroxide (powder LR grade) (73.60 g) andmethanol (100 ml) were added under stirring. The reaction mixture wasleft under a nitrogen atmosphere and stirred at room temperature (about25° C. to about 30° C.) for an hour. 1-bromo-3-methyl-2-butene (274 gm)was added to the reaction mixture and it was observed that thetemperature rose to about 40° C. The reaction mixture was heated toreflux and maintained for about 12 hours. After completion of thereaction as determined by HPLC, the methanol was distilled out fromreaction mixture under vacuum at a temperature below 60° C. Ethylenedichloride (1500 ml) and water (1000 ml) were added to the residue. Theorganic layer was separated and washed with a 5% sodium hydroxide (600ml) solution, and then water (3×600 ml) until the pH was about 7. Theorganic layer was then washed with a brine solution (700 ml). Theethylene dichloride was distilled out until the moisture content wasless than 0.1%.

Preparation of 4,4-dimethylthiochroman

In a 5 L 4-neck round bottom flask, ethylene dichloride (1500 ml) wasadded to the phenyl-3-methylbut-2-enyl sulfide from the previous step.Phosphorous pentoxide (200 gm) was added to the reaction mixture at atemperature ranging from about 25° C. to about 35° C. under stirring.Ortho phosphoric acid (174 ml) was added carefully under nitrogen. Thereaction mixture was heated to reflux, a temperature of about 80° C. toabout 90° C. and maintained at that temperature for about 12 hours.After completion of the reaction as determined by HPLC, the reactionmass was cooled to a temperature ranging from about 25° C. to about 35°C. and water (2000 ml) was slowly added to the reaction mass. Theorganic layer was separated, and the aqueous layer was extracted withEDC (2 L×2). The organic layers were combined and washed with saturatedsodium bicarbonate solution (2 L×2) and water (1.5 L×2) until the pH wasabout 7. This was followed by a washing with a brine solution (1.5 L).The EDC layer was distilled out under reduced pressure below atemperature of about 70° C. until the moisture content was less than0.1%. EDC (2 L) was added to the residue and taken for the next stepwithout further purification

Preparation of 4,4-dimethyl-6-acetylthiochroman

In a 5 L 4-neck round bottom flask, EDC (2 L) was added to the4,4-dimethylthiochroman from the previous step. The contents werestirred and cooled to a temperature of about −10° C. Aluminum chloride(252 g) was slowly added to the reaction mixture. Acetyl chloride (152.7g) was added at a temperature ranging from about −10° C. to about −5° C.over about 1.5 hours. After the addition, the reaction mixture wasmaintained at a temperature ranging from about −5° C. to about 0° C. forabout 2 hours. The reaction was monitored by TLC. [If the reaction isincomplete as determined by TLC, bring the reaction mixture to atemperature ranging from about 25° C. to about 35° C. under stirring forabout 4 hours.] The reaction mixture was quenched with ice (4.87 kg) andhydrochloric acid (1.63 L), and the reaction mass was stirred for about30 minutes. EDC (2.5 L) was added to the reaction mass. The layers wereseparated. The aqueous layer was extracted with MDC (2×2 L). The organiclayers were combined and washed with 5% sodium bicarbonate solution (2×2L) and water (2×2 L) until the pH is about 7. This was followed by awashing with brine (1.5 L). The EDC and MDC layer were distilled outunder reduced pressure until the moisture content was less than about0.1%. There was a residual volume of about 3 L.

It will be understood that various modifications may be made to theembodiments disclosed herein. Therefore the above description should notbe construed as limiting, but merely as exemplifications of preferredembodiments. For example, the functions described above and implementedas the best mode for operating the present invention are forillustration purposes only. Other arrangements and methods may beimplemented by those skilled in the art without departing from the scopeand spirit of this invention. Moreover, those skilled in the art willenvision other modifications within the scope and spirit of the claimsappended hereto.

1. A β-chloro vinyl carbonyl compound of the general formula:

wherein R is hydrogen or a hydrocarbyl of from 1 to about 15 carbonatoms.
 2. The β-chloro vinyl carbonyl compound of claim 1, wherein R ishydrogen.
 3. The β-chloro vinyl carbonyl compound of claim 1, wherein Ris a hydrocarbyl group of 1 to about 15 carbon atoms.
 4. The β-chlorovinyl carbonyl compound of claim 1, wherein R is an alkyl group of 1 to6 carbon atoms.
 5. The β-chloro vinyl carbonyl compound of claim 1,wherein R is a phenyl group.
 6. The β-chloro vinyl carbonyl compound ofclaim 1, having a purity of about 98%.
 7. A process for the preparationof a β-chloro vinyl carbonyl compound of the general formula I:

wherein R is hydrogen or a hydrocarbyl of from 1 to about 15 carbonatoms, the process comprising reacting a4,4-dimethyl-6-acetylthiochroman of the formula II

with an acid chloride and an amido-group containing compound of thegeneral formula III

wherein R has the aforestated meanings and R¹ and R² can be the same ordifferent and are hydrocarbyls of from 1 to about 15 carbon atoms or R¹and R² together with the nitrogen atom to which they are bonded arejoined together to form a heterocyclic group, optionally containing oneor more additional heterocyclic atoms, or one of R¹ and R² together withthe nitrogen atom to which it is bonded are joined together with thecarbonyl radical to form a heterocyclic group, optionally containing oneor more additional heterocyclic atoms to provide the β-chloro vinylcarbonyl compound of formula I.
 8. The process of claim 7, wherein theacid chloride is selected from the group consisting of phosphorousoxychloride, thionyl chloride, phosgene, oxalyl chloride and mixturesthereof.
 9. The process of claim 7, wherein the acid chloride isphosphorous oxychloride.
 10. The process of claim 7, wherein R ishydrogen and R¹ and R² each are hydrocarbyl groups of 1 to about 15carbon atoms.
 11. The process of claim 7, wherein R is hydrogen and R¹and R² each are hydrocarbyl groups of 1 to about 12 carbon atoms. 12.The process of claim 7, wherein R is hydrogen and R¹ and R² each arehydrocarbyl groups of 1 to 6 carbon atoms.
 13. The process of claim 7,wherein R is hydrogen and R¹ and R² together with the nitrogen atom towhich they are bonded are joined together to form a heterocyclic group.14. The process of claim 7, wherein R is a hydrocarbyl group of from 1to about 15 carbon atoms and R¹ and R² are independently hydrocarbylgroups of from 1 to about 15 carbon atoms.
 15. The process of claim 7,wherein R is a hydrocarbyl of from 1 to about 15 carbon atoms and R¹ andR² together with the nitrogen atom to which they are bonded are joinedtogether to form a heterocyclic group.
 16. The process of claim 7,wherein the amido-group containing compound is selected from the groupconsisting of dimethyl formamide, N -methyl formanilide, N-formylpiperidine, N-formyl morpholine, dimethyl acetamide, N -methylpyrrolidone, N,N-dimethyl benzamide and mixtures thereof.
 17. Theprocess of claim 7, wherein the amido-group containing compound ispresent in an amount of about 45 to about 90 weight percent, based onthe total weight of the reaction mixture.
 18. The process of claim 7,wherein the amido-group containing compound is present in an amount ofabout 55 to about 75 weight percent, based on the total weight of thereaction mixture.
 19. The process of claim 7, wherein the acid chlorideis present in a ratio of about 1:3 (w/v) to about 1:5 (w/v) with respectto the 4,4-dimethyl-6-acetylthiochroman.
 20. The process of claim 7,wherein the acid chloride is phosphorous oxychloride and the amido-groupcontaining compound is dimethyl formamide.